The prevalence of obesity is burgeoning in the United States. As a result, obesity-related metabolic disorders that confer increased CVD risk, including diabetes, dyslipidemia, and hypertension are reaching epidemic proportions. Susceptibility to the adverse metabolic consequences of obesity varies widely in the population: modest increases in adiposity lead to severe metabolic decompensation in some individuals, whereas others maintain a normal metabolic profile despite severe obesity. The overall goal of this project is to identify specific genetic mechanisms that account for the variability of metabolic responses to excess body weight and to evaluate the therapeutic potential of agents that target these mechanisms. The study includes three complementary strategies: First, we will sequence selected candidate genes in a large, multi-ethnic population (The Dallas Heart Study) in which each participant has undergone extensive metabolic characterization and relate the phenotypes to selected genotypes. Our focus will be on two groups of genes: 1) genes encoding circulating proteins that carry metabolic signals between the brain, liver, adipose tissue, and intestine ('metabokines'), and 2) genes encoding selected transcriptional regulatory molecules than respond to metabolic signals ('cellular metabolic regulators'). Included in these studies are genes being mechanistically interrogated in Projects 1-3. Second, we will use genome-wide methods as unbiased approaches toward the discovery of new genes and sequence variants that contribute to inter-individual differences in the metabolic responses to obesity. Third, we will collaborate with investigators in Projects 4 & 5 and perform detailed studies of glucose and lipid metabolism in both mice and humans to elucidate the mechanistic basis for genetic variation in susceptibility to the adverse metabolic consequences of obesity. This ambitious, interdisciplinary program leverages our established strengths in pairing careful phenotypic characterization with comprehensive genetic analyses in humans to discover new genes and sequence variations contributing to metabolic traits. In addition we have established collaborations that provide access to large, prospective population studies in which the effects of genetic sequence variants can be rigorously validated. These collaborations, together with the complementary expertise of our collaborators in Projects 1-5 greatly expand the scientific scope of our studies and increases our potential to identify new therapeutic targets and approaches to prevent and treat the adverse metabolic consequences of obesity.